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Mechanisms of development of multiple endocrine neoplasia type 2 and Hirschsprung's disease by ret mutations
M Takahashi1, N Asai, T Iwashita
1Department of Pathology, Nagoya University School of Medicine, Japan.
Abstract:
The ret proto-oncogene encodes a receptor tyrosine kinase whose ligands belong to the glial cell line-derived neurotrophic factor (GDNF) protein family. Its germline mutations are responsible for the development of multiple endocrine neoplasia (MEN) types 2A and 2B and Hirschsprung's disease (HSCR). MEN2A and MEN2B mutations result in the constitutive activation of Ret by different molecular mechanisms. MEN2A mutations involve cysteine residues present in the Ret extracellular domain and induce disulfide-linked Ret dimerization on the cell surface. MEN2B mutations were identified in methionine 918 in the tyrosine kinase domain and activate Ret without dimerization, probably due to a conformational change of its catalytic core region. In contrast to MEN2 mutations, HSCR mutations represent loss of function mutations. We found that most of HSCR mutations detected in the extracellular domain impair the Ret cell surface expression. More interestingly, ret mutations in cysteines 618 and 620 were reported in several families who developed both MEN2A and HSCR. It was suggested that these mutations might have two biological effects on Ret function, leading to the development of different clinical phenotypes in the same patients.
Insights
Germline mutations in the ret proto-oncogene cause multiple endocrine neoplasia (MEN) and Hirschsprung
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- The ret proto-oncogene encodes a receptor tyrosine kinase involved in development.
- Germline mutations in ret are linked to multiple endocrine neoplasia (MEN) types 2A and 2B, and Hirschsprung's disease (HSCR).
Purpose of the Study:
- To elucidate the molecular mechanisms underlying Ret activation in MEN2A and MEN2B.
- To understand the loss-of-function mechanisms of Ret in HSCR.
- To investigate Ret mutations associated with both MEN2A and HSCR phenotypes.
Main Methods:
- Analysis of Ret proto-oncogene mutations.
- Investigating Ret protein expression and dimerization.
- Correlating specific mutations with clinical phenotypes (MEN2A, MEN2B, HSCR).
Main Results:
- MEN2A mutations activate Ret via dimerization through extracellular cysteine residues.
- MEN2B mutations activate Ret through conformational changes in the tyrosine kinase domain.
- HSCR mutations often impair Ret cell surface expression, leading to loss of function.
- Specific Ret mutations (Cys618, Cys620) can lead to both MEN2A and HSCR, suggesting dual biological effects.
Conclusions:
- Ret mutations have diverse functional consequences, from constitutive activation to loss of function.
- The location and type of ret mutation dictate the resulting clinical phenotype.
- Understanding these genotype-phenotype correlations is crucial for diagnosing and managing associated diseases.